Abstract Congenital long QT syndrome (LQTS) is an inherited disease that affects otherwise healthy individuals and carries an increased risk of sudden death due to cardiac arrhythmia. LQTS affects 1 in 2500 individuals and results in 4,000 U.S. deaths annually. However, despite significant advances in our understanding of the fundamental biology, treatment options remain poor. All patients with LQTS are treated with beta-blockers in an effort to reduce the risk of fainting or sudden death. Beta-blockers do not correct the underlying QT interval prolongation, but help reduce the triggers of arrhythmias. Twenty-five percent of LQTS subjects will have cardiac events despite beta-blockers and in 5% that event is sudden death. For those patients who survive events on beta-blockers, implantable defibrillators (ICDs) are recommended. Such patients are often young, compounding the adverse effects of ICD therapy, with multiple ICD battery changes, spurious ICD shocks and lead revisions over their lifetimes. Therapies that correct the underlying physiology would be eagerly accepted to reduce ongoing risk of arrhythmias. Previous efforts to develop QT shortening drugs have been unsuccessful, in part due to excessive shortening of the QT interval. Such ?overshortening? causes short QT syndrome which can be as bad as or worse than long QT syndrome. Therefore any candidate drug for LQTS must have a means of limiting the QT shortening effect. In 2011, our laboratory discovered a novel class of small molecule compounds with beneficial activity in a zebrafish model of long QT syndrome. Since that time we have moved this compound class forward in the following ways: 1) Established efficacy in zebrafish, guinea pig, rabbit models, and in human stem cell models of LQTS, 2) Conducted a preliminary structure activity relationship study, improving potency 50-fold, 3) Conducted preliminary experiments that demonstrate a safety profile of self-limited action that distinguishes our compound class from prior therapeutic approaches to LQTS, and 4) Identified a key objective for our hit compound series in improving in vivo short circulating half-life, and 5) Identified 2MMB as an activator of the adenosine sensitive potassium current IKATP. It is our goal to further develop this class of compounds into a therapeutic treatment for long QT syndrome through the following specific aims: 1) To perform mechanistic studies of the molecular mechanism of action of 2MMB, 2) To explore in greater detail the safety profile for the benzanilide class of compounds, and 3) To perform structure activity studies of 100 new structural analogs of 2MMB. We have assembled the team and the tools to conduct these experiments which will provide critical information regarding the feasibility and safety of a novel therapeutic approach to the treatment of long QT syndrome. The ultimate deliverable is a novel therapy for this life-threatening syndrome that claims the lives of otherwise healthy young individuals.